ArticleCommunications biology2022
Oligomerization, trans-reduction, and instability of mutant NOTCH3 in inherited vascular dementia.
Article in Communications biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 12 citations in OpenAlex.
- ProNotch converts extracellular protease activity into programmable transcriptional outputs.bioRxiv : the preprint server for biology · 2026Article
- NOTCH3 CADASIL Variant Receptor Aggregation Requires NOTCH3 Wild-Type Receptors: Identification of Highly Selective Inhibitors That Block the Process.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Cysteine-reactive mitigators of small vessel disease-related NOTCH3 mutants.Scientific reports · 2026Article
- NOTCH3 Mutations in CADASIL: a multicellular perspective on neurodegeneration.Cell communication and signaling : CCS · 2026Review
- Synergistic effects of mutation and glycosylation on disease progression.Frontiers in molecular biosciences · 2025Review
- The N-acetylglucosaminyltransferase Radical fringe contributes to defects in JAG1-dependent turnover and signaling of NOTCH3 CADASIL mutants.The Journal of biological chemistry · 2024Article
- Transcription of microRNAs is regulated by developmental signaling pathways and transcription factors.Frontiers in cell and developmental biology · 2024Article
- Structural changes in NOTCH3 induced by CADASIL mutations: Role of cysteine and non-cysteine alterations.The Journal of biological chemistry · 2023Article
- Update on the Epidemiology, Pathogenesis, and Biomarkers of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.Journal of clinical neurology (Seoul, Korea) · 2023Review
- Oligomerization, trans-reduction, and instability of mutant NOTCH3 in inherited vascular dementia.Communications biology · 2022Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Cerebral small vessel disease (SVD) is a prevalent disease of aging and a major contributor to stroke and dementia. The most commonly inherited SVD, CADASIL, is caused by dominantly acting cysteine-altering mutations in NOTCH3. These mutations change the number of cysteines from an even to an odd number, but the impact of these alterations on NOTCH3 protein structure remain unclear. Here, we prepared wildtype and four mutant recombinant NOTCH3 protein fragments to analyze the impact of CADASIL mutations on oligomerization, thiol status, and protein stability. Using gel electrophoresis, tandem MS/MS, and collision-induced unfolding, we find that NOTCH3 mutant proteins feature increased amounts of inappropriate disulfide bridges, reduced cysteines, and structural instability. Presence of a second protein factor, an N-terminal fragment of NOTCH3 (NTF), is capable of further altering disulfide statuses of both wildtype and mutant proteins, leading to increased numbers of reduced cysteines and further destabilization of NOTCH3 structure. In sum, these studies identify specific cysteine residues alterations and quaternary structure induced by CADASIL mutations in NOTCH3; further, we validate that reductive factors alter the structure and stability of this small vessel disease protein.
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